AREDS2: Seeking to Improve Performance and Safety

Data from the follow-up study suggest that doctors and patients should proceed with caution.

AREDS2: Seeking to Improve Performance and Safety

Data from the follow-up study suggest that doctors and patients should proceed with caution.


With four primary treatment groups, each containing four subgroups, the AREDS2 study1 illustrates how complex it can be to simplify something.

The first Age-Related Eye Disease Study found that patients taking the original AREDS supplement formulation — 500 mg of vitamin C, 400 IU of vitamin E, 15 mg of beta-carotene, 80 mg of zinc, and 2 mg of copper — were 25% less likely to progress to advanced AMD than patients who received a placebo over the five-year study period between 2001 and 2006.2

Evidence outside that trial suggested the possibility of improving the performance and/or safety of the original AREDS formula. Observational data suggested that diets high in lutein, zeaxanthin, and omega-3 fatty acids might reduce progression to advanced AMD.3-6

In addition, separate research also suggested that beta-carotene, which was part of the original AREDS formula, might increase the risk of lung cancer in some smokers or former smokers.7-8

The appropriate dosage of zinc also received further attention in AREDS2. The 80-mg dose of zinc in the original study was higher than levels seen to cause side effects in some patients.


As a result of these findings, AREDS2 sought to improve the performance and safety of the original formula by studying additional supplement formulations to investigate these issues:

    • whether adding omega-3 fatty acids, specifically 350 mg of docosahexaenoic acid (DHA) and 650 mg of eicosapentaenoic acid (EPA), might further reduce progression to advanced AMD;

    • whether removing beta-carotene, which has been associated with an increased lung cancer risk in smokers and former smokers, would affect the rate of AMD progression;

    • whether adding lutein and zeaxanthin to the formulation might reduce AMD progression; and

    • whether the amount of zinc, which was reported to cause side effects such as stomach upset, could be reduced without diminishing its protective effect.


AREDS2 enrolled four primary treatment groups (Table, page 46). One group replicated the original AREDS treatment group. A second replicated the original treatment group, except that it reduced the daily dose of zinc from 80 mg to 25 mg. The other two primary groups removed beta-carotene from the formula, with one receiving 80 mg of zinc and the other 25 mg.

Table. AREDS2 Primary Treatment Groups


Original AREDS

No beta carotene

Reduced zinc

Reduced zinc/no beta carotene

Vitamin C

500 mg

500 mg

500 mg

500 mg

Vitamin E

400 IU

400 IU

400 IU

400 IU

Beta carotene

15 mg

15 mg


80 mg

80 mg

25 mg

25 mg


2 mg

2 mg

2 mg

2 mg

Each of the four groups was divided into four subgroups and patients received:

    lutein 10 mg/zeaxanthin 2 mg;

    omega-3 fatty acids: 350 mg DHA and 650 mg EPA;

    both of the above; or


Source: AREDS2

Each of the four primary groups were split into four subgroups, in which patients also received one of these additions to their formulations: 10 mg of lutein and 2 mg of zeaxanthin; 350 mg of the omega-3 fatty acid DHA and 650 mg of EPA; both lutein and zeaxanthin and the omega-3 fatty acids; or placebo.

AREDS2 found no overall extra benefit from adding omega-3 fatty acids or the mixture of lutein and zeaxanthin to the primary formulations. Reducing the zinc in the formulations also had no significant effect on AMD progression in the study.

In a separate study also reported in May 2013,9 the AREDS2 researchers found that none of the AREDS2 formulations helped to reduce the risk of cataract formation, a question that the original AREDS trial did not study directly.


While the overall results of AREDS2 did not show a significant change in protection against AMD progression in the overall study population, results from two subgroups suggested that altering the formulations could improve results as well as streamline care.

“When we looked at just those participants in the study who took an AREDS formulation with lutein and zeaxanthin but no beta-carotene, their risk of developing advanced AMD over the five years of the study was reduced by about 18%, compared with participants who took an AREDS formulation with beta-carotene but no lutein or zeaxanthin,” Emily Chew, MD, PhD, said at the press conference discussing AREDS2 during the ARVO meeting last May. Dr. Chew is the lead author of the study and deputy director of the Division of Epidemiology and Clinical Applications at the National Eye Institute.

“Further analysis showed that participants with low dietary intake of lutein and zeaxanthin at the start of the study, but who took an AREDS formulation with lutein and zeaxanthin during the study, were about 25% less likely to develop advanced AMD compared with participants with similar dietary intake who did not take lutein and zeaxanthin,” she added.

AREDS2 did not address the reason why, but researchers have offered a theory. Lutein, zeaxanthin, and beta-carotene are all carotenoids. Because carotenoids compete with each other for absorption in the body, beta-carotene might have masked the beneficial effects of lutein and zeaxanthin, Dr. Chew noted.


While adding lutein and zeaxanthin did not provide additional protective benefit in the overall AREDS2 study — only in the two smaller subgroups described — replacing beta-carotene in the original AREDS formulation with lutein and zeaxanthin in AREDS2 provided essentially the same benefit across those groups.

Some of the AREDS2 data support the idea that patients can retain the same protective effect against AMD progression using lutein and zeaxanthin, without exposing smokers and former smokers to the increased lung cancer risk associated with beta-carotene.

“Removing beta-carotene simplifies things,” says AREDS2 coauthor Wai T. Wong, MD, who is part of the NEI retinal disease unit. “We have identified a formulation that should be good for everyone regardless of smoking status.”

Many patients with AMD have a history of smoking. While the absolute risk of developing lung cancer may be small, reducing the relative risk is worthwhile, Dr. Chew says.


The combination of maintaining the same protective benefit against AMD progression, avoiding beta-carotene in patients with a smoking history, and a clear, consistent message to give all her patients helped lead Dr. Chew to this approach for these patients.

    No evidence of AMD on examination. Dr. Chew recommends a diet rich in spinach and fish, supplemented with a daily multivitamin.

    Evidence of early or moderate AMD. She recommends the same healthy diet and a multivitamin supplemented with the AREDS2 formulation, with lutein and zeaxanthin but without beta-carotene.

    Evidence of advanced AMD. Dr. Chew does not recommend adding an AREDS2 formulation vitamin, because doing so has not been shown to prevent progression in either of the AREDS studies.

Dr. Chew also gives her patients printed material that explains the AREDS research and her approach to supplements.

In short, the data suggest that replacing beta-carotene with lutein and zeaxanthin makes the formulation safer without diminishing its protective benefit in reducing progression to advanced AMD. Further, that formulation appears appropriate for all patients, regardless of whether they are or were smokers.

While Dr. Chew and others are following the approach to remove beta-carotene from their patients’ diets, some in the field suggest that people who have never smoked and are taking an original AREDS formulation supplement should keep taking it, based on their lower risk of lung cancer as nonsmokers and the longer clinical track record of the original AREDS formula.


While reducing zinc from 80 mg to 25 mg per day in the studies did not significantly affect the protective effects of those formulations, Dr. Chew notes the available data do not make clear how much zinc is necessary or optimal to prevent AMD progression.

The NEI says that reports have emerged of mild side effects, such as upset stomach, in some people taking zinc supplements. However, this problem was not reported in the AREDS studies.

In addition, a more recent analysis of one arm of AREDS210 found that zinc may have had a negative effect in AMD patients with specific genetic factors — specifically one or two complement factor H (CFH) risk alleles.

This analysis concluded that study subjects with no CFH risk alleles but with one or two ARMS2 (age-related maculopathy sensitivity 2) risk alleles derived maximum benefit from zinc-only supplements. However, those with one or two CFH risk alleles but no ARMS2 risk alleles were at risk for increased progression to advanced AMD with zinc supplementation. They derived maximum benefit from antioxidant-only supplementation.

At least two AREDS2-based supplement formulations have dropped zinc, based on these published data.


While omega-3 fatty acids did not improve protection against AMD in AREDS2, other studies have found them beneficial to cardiac health. Researchers have emphasized that omega-3 fatty acids should remain part of a healthy diet. Dr. Chew calls diet the “front-line therapy” in eye health, stressing fish and dark green, leafy vegetables, such as spinach and kale.

While explaining the AREDS2 study and its results to patients can be complicated, navigating the world of vitamin and mineral supplements can also be daunting. Because the FDA regulates vitamins and supplements less vigorously than it does pharmaceuticals and medical devices, manufacturers can and do easily create and market new formulations.

Vitamin manufacturers also market broader multivitamin products containing varying doses of all or some of the vitamins and minerals AREDS and AREDS2 studied. Ocular supplements also are often marketed as general eye health formulas. Dozens of such supplement products are for sale online.


Dr. Chew recommends the specific AREDS2 formulation that replaces beta-carotene with lutein and zeaxanthin because it has been rigorously studied and can be used regardless of a patient’s smoking status. It also helps to streamline the discussion for both the ophthalmologist and the patient when so many supplement products are available.

“It makes it simpler for the patient, and you could have one formulation on the shelf,” Dr. Chew says.

While it may have taken 16 study arms to get there, Dr. Chew believes the AREDS2 data could streamline clinicians’ discussions with patients and provide appropriate treatment to most patients at risk for AMD who are candidates for supplementation. RP


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2. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report number 9. Arch Ophthalmol. 2001;119:1439-1452.

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